Dual Drug Delivery Device

ABSTRACT

A liquid delivery apparatus for the intrathecal delivery of one or more medications to a patient is disclosed. The liquid delivery apparatus generally includes a liquid reservoir, a liquid metering unit fluidly connected to the liquid reservoir, and a catheter delivery tube fluidly connected to the liquid metering unit. Preferably, the liquid delivery apparatus includes two or more liquid reservoirs. In various embodiments, the liquid reservoir includes a deformable balloon and a compressive sleeve spring as a pressure source, the liquid metering unit is a piezoelectrically actuated microvalve, and/or diagnostic sensors are included in the apparatus. The disclosed apparatus are compact, volume-efficient, energy-efficient, capable of delivering accurate fluid volumes, and address problems associated with multi-medication therapies. Methods of operating the liquid delivery apparatus are also disclosed.

CROSS REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. provisional patentapplication Ser. No. 61/018,607 filed Jan. 2, 2008, the disclosure ofwhich is incorporated herein by reference, is claimed.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

Research relating to the claimed subject matter was supported in part bythe United States government under Grant No. NNA05CP85G awarded by theNational Aeronautics and Space Administration. The government may havecertain rights in the claimed subject matter.

BACKGROUND

The disclosure generally relates to liquid delivery apparatus and, morespecifically, to implantable drug delivery devices. Implantable drugdelivery devices are medical devices used to administer an infusate(e.g., medications/drugs, chemicals, solutions) to a predefined locationin a patient (e.g., intrathecal delivery). The devices can be used totreat chronic pain, spasticity, or other medical conditions that wouldbenefit from controlled administration of an infusate.

Chronic pain is a persistent condition in which the source of the paincannot be treated. It afflicts an estimated 100 million people in theUnited States with annual costs exceeding $100 billion. W. A. Visser,“Combined spinal epidural anaesthesia,” Anaesthesia, vol. 54, p. 300,March 1999. It is often a symptom of incurable or intractable conditionslike cancer, but it can also arise from severe trauma, limb loss, orother combat-related injuries. P. S. Tumber et al., “The control ofsevere cancer pain by continuous intrathecal infusion and patientcontrolled intrathecal analgesia with morphine, bupivacaine andclonidine,” Pain, vol. 78, pp. 217-220, December 1998; M. Carmichael,“The changing science of pain,” Newsweek, vol. 149, pp. 40-47, Jun. 4,2007; T. J. Smith et al., “Pain management, including intrathecalpumps,” Curr. Pain Headache Rep., vol. 9, pp. 243-248, August 2005. Ifthe chronic pain condition is severe, it may be treated with surgery,spinal cord stimulation, or the implantation of an intrathecal drugpump.

The technological aspects of intrathecal drug pumps have remainedrelatively unchanged for over a decade. Conventional intrathecal pumpsconsist of a battery-powered, programmable pump which is connected to orincorporates an infusate reservoir. The pump is implanted under tissuein the patient's abdomen and connected to a catheter that continues to ainfusion/drug delivery point (e.g., a spinal entry point). K. Knight,“Implantable Intrathecal Pumps for Chronic Pain: Highlights andUpdates,” Croat. Med. J., vol. 48, pp. 22-34, 2007.

In some intrathecal pumps, an electrically powered mechanism pumps theinfusate from the reservoir to the infusion point. Such pumps can beused to control the dosage of the infusate and variable dosing protocolscan be followed.

In other intrathecal pumps, the infusate is driven to the infusion pointby a propellant exerting a positive and constant pressure on theinfusate reservoir. Such devices require large rigid housings to containboth the infusate reservoir and the propellant. While such gas-drivenpumps can be cost-effective, they suffer from infusate delivery problemswhen environmental factors change the pressure that the propellantexerts on the infusate reservoir.

The problem of variable flow in gas-driven pumps has been addressedusing drive-spring diaphragms, for example as disclosed in U.S. Pat. No.6,666,845. In such systems, a drive spring provides the constantpressure to collapse the infusate reservoir. Similar to the gas-drivenpumps, the spring-driven pumps require a large and rigid housing.

A limitation of commercially available intrathecal pumps is that theyprovide only a single infusate reservoir, while preferred methods forpain management specify the administration of multiple medications withdifferent dosing and delivery protocols. However, such single-reservoirsystems require drugs to be mixed in a fixed ratio and dispensed from asingle reservoir, which can be problematic with drugs that areincompatible and/or unstable when stored in a mixture for an extendedperiod. Moreover, single-reservoir systems cannot independently controlthe relative flow rates of individual drugs.

The large, rigid nature of conventional intrathecal pumps limits theapplicability of the technology. The utility of an intrathecal devicecan be represented by its volume efficiency. The volume efficiency isthe ratio of the volume of the infusate reservoir when full to thevolume of the entire intrathecal pump device. As the volume efficiencyis limited by the architecture of the pump and its component sizes,improvements in volume efficiency in conventional intrathecal pumps islimited. A low volume efficiency can restrict the use of intrathecalpumps, for example preventing their use in pediatric applications, whichrequire a significantly smaller pump than that which can be used in anadult.

Thus, there is need for an intrathecal drug delivery device that has ahigh volume efficiency, is volume-scalable, and can independentlydeliver multiple drugs.

SUMMARY

This need is addressed by the design and use of an inventive liquiddelivery apparatus. The apparatus generally include one or more liquidreservoirs, a liquid metering unit fluidly connected to each liquidreservoir, and a catheter delivery tube fluidly connected to the liquidmetering unit(s). The disclosed apparatus arc compact, volume-efficient,energy-efficient, and capable of delivering accurate fluid flowrates/volumes. When the liquid delivery apparatus include two or morefluid reservoirs, the fluid flow rate from each reservoir can beindependently controlled, and complications due to medicationincompatibilities can be avoided.

In an embodiment, a liquid delivery apparatus includes a liquid deliverypathway, the liquid delivery pathway including a liquid reservoir, aliquid metering unit fluidly connected to the liquid reservoir, and acatheter delivery tube fluidly connected to the liquid metering unit.The liquid reservoir further includes a deformable balloon and apressure source selected from the group consisting of a compressivesleeve spring and an electrolytic fluid cell. Preferably, the liquiddelivery apparatus includes two or more liquid delivery pathways.Preferably, the liquid metering unit includes a throttle, and the liquiddelivery pathway further includes a means for measuring the volume ofthe liquid reservoir (e.g., a pressure sensor fluidly connected to theliquid reservoir between the liquid reservoir and the liquid meteringunit throttle). More preferably, the liquid delivery apparatus includesa liquid delivery control module having a microprocessor electricallyconnected to the throttle and the means for measuring the volume of theliquid reservoir and a battery electrically connected to themicroprocessor. When the liquid delivery apparatus includes two or moreliquid delivery pathways, if it preferable for the microprocessor to becapable of independently controlling liquid flow through each liquiddelivery pathway. The throttle can be a piezoelectrically actuatedmicrovalve, in which case the microvalve preferably includes a firstplate (e.g., a silicon-on-insulator substrate) and a second plate (e.g.,glass) spaced apart and joined together to define a flow path having aninlet fluidly connected to the liquid reservoir and an outlet fluidlyconnected to the catheter delivery tube and a piezoelectric material(e.g., lead zirconium titanate) external to the flow path and in contactwith the first plate. The compressive sleeve spring is preferably madefrom a piezoresistive material, for example an alloy of copper,chromium, and nickel. Optionally, the liquid delivery apparatus caninclude various access ports, for example a refill port for the liquidreservoir and/or a bolus port for the catheter delivery tube.

In another embodiment, a liquid delivery apparatus includes a pluralityof liquid delivery pathways, where each liquid delivery pathway includesa liquid reservoir, a piezoelectrically actuated microvalve fluidlyconnected to the liquid reservoir, and a catheter delivery tube fluidlyconnected to the piezoelectrically actuated microvalve. The microvalvepreferably includes a first plate (e.g., a silicon-on-insulatorsubstrate) and a second plate (e.g., glass) spaced apart and joinedtogether to define a flow path having an inlet fluidly connected to theliquid reservoir and an outlet fluidly connected to the catheterdelivery tube and a piezoelectric material (e.g., lead zirconiumtitanate) external to the flow path and in contact with the first plate.Preferably, the liquid delivery pathway further includes a means formeasuring the volume of the liquid reservoir (e.g., a pressure sensorfluidly connected to the liquid reservoir between the liquid reservoirand the liquid metering unit throttle). The liquid reservoir can includea deformable balloon and a pressure source selected from a compressivesleeve spring (e.g., a copper, chromium, and nickel alloy), a torsionspring, and an electrolytic fluid cell. Preferably, the liquid deliveryapparatus includes a liquid delivery control module having amicroprocessor electrically connected to the piezoelectrically actuatedmicrovalve and the means for measuring the volume of the liquidreservoir for each of the liquid delivery pathways and a batteryelectrically connected to the microprocessor.

In yet another embodiment, a liquid delivery apparatus includes a liquiddelivery pathway and a sensor selected from the group consisting of aflow meter fluidly connected to the liquid delivery pathway, anaccelerometer, and combinations thereof. The liquid delivery pathwayfurther includes a liquid reservoir, a liquid metering unit fluidlyconnected to the liquid reservoir, and a catheter delivery tube fluidlyconnected to the liquid metering unit. Preferably, the liquid deliveryapparatus includes two or more liquid delivery pathways, and the sensorincludes an accelerometer (e.g., a shock senor or a plurality of shocksensors). The liquid reservoir can include a deformable balloon and apressure source selected from a compressive sleeve spring, a torsionspring, and an electrolytic fluid cell, the liquid metering unit caninclude a throttle, and the liquid delivery pathway can include a meansfor measuring the volume of the liquid reservoir (e.g., a pressuresensor fluidly connected to the liquid reservoir between the liquidreservoir and the liquid metering unit). Preferably, the liquid deliveryapparatus includes a liquid delivery control module having amicroprocessor electrically connected to the throttle and the means formeasuring the volume of the liquid reservoir and a battery electricallyconnected to the microprocessor.

In another embodiment, a liquid delivery apparatus includes a liquidreservoir including a deformable balloon having an interior volume andat least one deformable interior wall in the interior volume, such thatthe at least one deformable interior wall defines a plurality ofreservoir chambers in the interior volume. The liquid delivery apparatusfurther includes a plurality of liquid metering units, each of which isfluidly connected to one of the reservoir chambers, and a plurality ofcatheter delivery tubes, each of which is fluidly connected to one ofthe liquid metering units. Preferably, the liquid reservoir furtherincludes a pressure source selected from a compressive sleeve spring, atorsion spring, and an electrolytic fluid cell; each liquid meteringunit includes a throttle; and, the liquid delivery apparatus includes ameans for measuring the volume of the liquid remaining in the reservoirchambers. The liquid delivery apparatus preferably also includes aliquid delivery control module having a microprocessor electricallyconnected to the throttle and the means for measuring the volume of theliquid remaining in the reservoir chambers and a battery electricallyconnected to the microprocessor.

For any of the disclosed liquid delivery apparatus having two or moreliquid reservoirs, methods of delivering a plurality of medications to apatient in need thereof are disclosed. The methods generally includeproviding the liquid delivery apparatus with a microprocessorelectrically connected to the liquid metering units and, optionally, ameans for measuring the volumes of the liquid reservoirs. The liquiddelivery apparatus is then charged with a plurality of medications, suchthat at least one liquid reservoir contains a medication that isdifferent from the medication contained in another liquid reservoir.Finally, the plurality of medications is delivered the patient atindependently controlled flow rates by independently adjusting eachliquid metering unit in response to a flow control program stored in themicroprocessor.

For the disclosed liquid delivery apparatus having two or more liquidreservoirs and an accelerometer, a method of optimizing the dosage levelof a plurality of medications to a patient in need thereof is disclosed.The method includes charging the liquid delivery apparatus with theplurality of medications, wherein at least one liquid reservoir containsa first medication that is different from a second medication containedin another liquid reservoir; monitoring a first activity level of thepatient to identify a first optimum dosage level of the firstmedication; monitoring a second activity level of the patient toidentify a second optimum dosage level of the second medication; and,delivering to the patient the first medication at the first optimumdosage level and the second medication at the second optimum dosagelevel. Preferably, the step of monitoring the first activity levelincludes delivering only the first medication to the patient at aplurality of first dosage levels, each of the first dosage levels beingdelivered for a preselected length of time; measuring the first activitylevel of the patient at each of the first dosage levels using theaccelerometer; and, selecting the first optimum dosage level based onthe first dosage level that provides the greatest first activity level.Similarly, the step of monitoring the second activity level includesdelivering only the second medication to the patient at a plurality ofsecond dosage levels, each of the second dosage levels being deliveredfor a preselected length of time; measuring the second activity level ofthe patient at each of the second dosage levels using the accelerometer;and, selecting the second optimum dosage level based on the seconddosage level that provides the greatest second activity level.

BRIEF DESCRIPTION OF THE DRAWINGS

For a more complete understanding of the disclosure, reference should bemade to the following detailed description and accompanying drawingswherein:

FIG. 1 is a perspective view of a liquid delivery apparatus according toan embodiment of the disclosure.

FIG. 2 is aside view of a liquid delivery pathway in the liquid deliveryapparatus of FIG. 1.

FIGS. 3 a to 3 d are views of a compressive sleeve spring and adeformable balloon in the liquid delivery apparatus of FIG. 1.

FIG. 4 is graph illustrating the relationship between the appliedpressure and the diameter of a reservoir in the liquid deliveryapparatus of FIG. 1.

FIGS. 5 a and 5 b are side views of an alternate embodiment of areservoir for a liquid delivery apparatus.

FIGS. 6 a to 6 j illustrate various alternative configurations of thegeneral components of the disclosed liquid delivery apparatus.

FIGS. 7 a to 7 c are graphs illustrating a method of optimizing thedosage level of a plurality of medications to a patient in need thereof.

FIG. 8 is a graph illustrating the actuation frequency of apiezoelectrically actuated microvalve throttle as a function of theaccuracy of the fluid flow rate delivered by the liquid deliveryapparatus of FIG. 1.

FIG. 9 is a graph illustrating the accuracy of a fixed-volume bolusdelivered by the liquid delivery apparatus of FIG. 1.

While the disclosed process and apparatus are susceptible of embodimentsin various forms, specific embodiments of the invention are illustratedin the drawings (and will hereafter be described) with the understandingthat the disclosure is intended to be illustrative, and is not intendedto limit the invention to the specific embodiments described andillustrated herein.

DETAILED DESCRIPTION

Disclosed herein are liquid delivery apparatus and processes using thesame. One embodiment of a liquid delivery apparatus 100 is illustratedin FIGS. 1 and 2. As illustrated, the liquid delivery apparatus 100includes two liquid delivery pathways 110 encased in an external housing102, although some embodiments can include a single liquid deliverypathway or more that two liquid delivery pathways. The external housing102 is preferably made from any rigid, biocompatible material, forexample a metal (e.g., titanium, aluminum, stainless steel) or a rigid,durable plastic. Each liquid delivery pathway 110 generally includes areservoir 120 containing a fluid that is enclosed by an internal housing104 (which can be made from the same or different material as theexternal housing 102) and is fluidly connected to a liquid metering unit160. The outlet of each liquid metering unit 160 is preferably fluidlyconnected to a single liquid delivery catheter 170. The liquid deliverycatheter 170 can be a single-lumen catheter, in which case the fluidsbeing delivered mix upon exiting the liquid metering unit 160.Alternatively, the liquid delivery catheter 170 can be a multi-lumencatheter, in which case the fluids being delivered remain segregated atleast until they reach the delivery site in a patient's body. The liquiddelivery catheter 170 can include a bolus port (e.g., an access line tothe catheter sealed with a septum or other re-sealable structure; notshown) allowing manual injection of a medication directly into thepatient, bypassing the liquid delivery apparatus 100. Preferably, theliquid delivery apparatus 100 also includes a liquid delivery controlmodule 180 to independently control each of the two liquid deliverypathways 110.

The liquid delivery apparatus 100 is preferably both compact andvolume-efficient. Because the liquid delivery apparatus 100 is intendedfor implantation into a human patient, the device should be as small aspractical for aesthetic purposes, for patient comfort, and to minimizethe invasiveness of the implantation procedure. For adult humanpatients, the liquid delivery apparatus 100 preferably has a totalvolume of about 120 ml or less, more preferably about 90 ml or less, andmost preferably about 80 ml or less. Because the liquid deliveryapparatus 100 can be scaled down for pediatric applications, smallertotal volumes are contemplated. For example, the liquid deliveryapparatus 100 preferably has a total volume ranging from about 20 ml toabout 120 ml, about 30 ml to about 90 ml, or about 40 ml to about 80 ml.Relatively small total volumes are possible because the liquid deliveryapparatus 100 is relatively volume-efficient, meaning that a substantialportion of the total device volume is allocated to the reservoir(s) 120and that the liquid delivery apparatus 100 can be operated at longerintervals between refilling the reservoir(s) 120. For example, theliquid delivery apparatus 100 preferably has a volume efficiency of atleast 0.35, more preferably at least about 0.4 or at least about 0.5,for example in a range of about 0.4 to about 0.8 or about 0.4 to about0.6.

Various elements, embodiments, and the operation of the disclosed liquiddelivery apparatus are described in more detail below.

Liquid Reservoirs

The reservoir 120 is not particularly limited and can include anystructure that is able to both retain and release its fluid contents.Generally, the reservoir 120 is designed so that it contracts andexpands with the discharge and refilling, respectively, of its fluidcontents. Suitable reservoir structures include deformable balloons,diaphragms, and expanding bellows. A swollen hydrogel also can serve asa suitable reservoir structure, being able to discharge its absorbedcontents in response to an external pressure, for example when encasedin an enclosure used to direct the output of the discharged contents.Fluid being delivered from the reservoir 120 exits via an outlet 144(e.g., a piece of flexible tubing fluidly connecting the reservoir 120to the liquid metering unit 160). The reservoir 120 preferably includesa refill port 134 (e.g., a septum or other re-sealable structure)allowing access to the reservoir 120 for recharging a depleted fluidreserve.

Preferably, the reservoir 120 includes a deformable balloon 130, forexample an inflatable structure like those used in balloon angioplastytreatments. The deformable balloon 130 can be made from any flexible,liquid-impermeable material, for example elastomeric polymers, withpolyethylene terephthalate (PET) being a particularly preferredmaterial. Preferably, the elasticity of the deformable balloon 130creates a pressure within the balloon 130 when the balloon 130 is filledwith a liquid and expands, which pressure should be sufficient to drivethe liquid through the outlet 144 in the balloon 130. Still further, thepressure supplied by the balloon 130 preferably does not significantlyvary between different discharge/refill cycles of the balloon 130, suchthat is the balloon 130 has a repeatable, known relationship forreservoir pressure as a function of reservoir volume. P(V).

The reservoir 120 preferably also includes a pressure source 140 todischarge fluid from the reservoir 120. In some embodiments, thereservoir 120 itself may provide the necessary pressure driving sourceto discharge fluid from the reservoir 120 (e.g., when the reservoir 120includes the elastic, deformable balloon 130). In other embodiments, theliquid metering unit 160 may provide a suction pressure (e.g., when itincludes a pump) sufficient to withdraw fluid from the reservoir 120 ata controlled rate. However, it is often preferable to include thepressure source 140 to provide a positive, controlled dischargepressure. Suitable pressure sources 140 are not particularly limited,for example including springs (e.g., compression sleeve springs andtorsion springs, described in more detail below), electrolytic fluidcells (e.g., using a liquid that vaporizes to form a pressurizing gasbubble in response to a current passed through the liquid), thermalfluid cells (e.g., using a liquid that vaporizes to form a pressurizinggas at physiological temperatures), swollen hydrogels, and gaseouspropellants. The use of electrolytic and thermal fluid cells to generatebubbles for pumping action is known, for example as described in Neagu,et al. “An electrochemical microactuator: principle and first results,”J. Microelectromechanical Sys., 5(1), March 1996 pp. 2-9 and S. Li, etal. “A single cell electrophysiological analysis device with embeddedelectrode,” Sensors and Actuators A (Physical), v. 134, n. 1, Feb. 28,2007, p. 20-6, both of which are herein incorporated by reference.

When the reservoir 120 has a deformable construction, the pressuresource 140 can simply act externally to the reservoir 120 to compressand contract the reservoir 120 while expelling the fluid contentsthereof. When the reservoir 120 has an at least partially rigidconstruction with a deformable or slidable boundary between the fluidcontents of the reservoir 120 and the pressure source 140, the pressuresource 140 can be used to push against the deformable or slidableboundary to expel the fluid contents of the reservoir 120 (e.g., a rigidtubular reservoir 120 having a slidable diaphragm opposite the reservoiroutlet 144).

As illustrated in FIGS. 1 and 2, a preferred pressure source 140 is acompressive sleeve spring 142. The compressive sleeve spring 142 is acylindrical spring in which the spring acts to provide a radially inwardcompressive force. Thus, when the compressive sleeve spring 142ensleeves a tubular shaped reservoir 120 (e.g., the deformable balloon130 as illustrated), the spring's compressive force provides thepressure to expel fluid from the reservoir 120. Preferably, thecompressive sleeve spring 142 is made from a metal alloy that isbiocompatible, corrosion resistant,durable, and/or has favorableelectrical properties. An example of a suitable metal alloy is aCo/Cr/Ni alloy that is commercially available under the name ELGILOY(available from Elgiloy Specialty Metals, Elgin, Ill.). The compressivesleeve spring 142 can be formed by laminating a sheet of the Co/Cr/Nialloy with photoresist, patterning the photoresist, and then chemicallyetching the alloy sheet. The etched alloy sheet is then rolled and fixedinto a cylindrical shape to form the compressive sleeve spring 142.

FIGS. 3 a-3 d illustrate the compressive sleeve spring 142 in variousstages. FIGS. 3 a and 3 b show the compressive sleeve spring 142 as theetched alloy sheet, in a relaxed and stretched state, respectively. FIG.3 c illustrates an 18.8 ml inflated deformable balloon 130 and a relaxedcompressive sleeve spring 142, while FIG. 3 d illustrates the samedeformable balloon 130 and compressive sleeve spring 142 in an ensleevedconfiguration. In the embodiment shown in FIGS. 3 a-3 d, the springs are100 μm thick, the spring beams are 150 μm wide, the mesh cell size is600 μm×6 mm, and the compressive sleeve spring 142 was formed from a 60mm×10 mm etched alloy sheet.

Similar to the deformable balloon 130, the compressive sleeve spring 142preferably provides a repeatable pressure-volume profile betweensubsequent discharge/refill cycles. That is, after the compressivesleeve spring 142 is conditioned (i.e., strained in the first instance),the spring constant for the radial compressive force of the compressivesleeve spring 142 is substantially constant and repeatable.

The repeatable pressure-volume profile of both the deformable balloon130 and the compressive sleeve spring 142 allows the determination ofthe reservoir 120 volume by measuring the reservoir 120 pressure. Byextension, pressure measurements at multiple time intervals permitsdetermination of the flow rate of fluid exiting the reservoir 120. FIG.4 illustrates a representative pressure-volume profile for the balloon130/spring 142 embodiment of FIG. 3 d. Specifically, FIG. 4 plots thediameter of a cylindrical deformable balloon 130 (i.e., which correlatesdirectly to the reservoir 120 volume (specifically, the volume of thefluid remaining in the reservoir 120)) as a function of the net pressureapplied by the combination of the deformable balloon 130 and thecompressive sleeve spring 142. At low volumes, the balloon 130 diameterchanges linearly with a high slope (e.g., from 12 mm to 19 mm asillustrated) as the compressive sleeve spring 142 provides the dominantpressurizing force. At higher volumes (e.g., above 19 mm asillustrated), the elasticity of the balloon 130 material begins todominate the pressure generation curve. When fully charged, theillustrated deformable balloon 130 is about 20 mm in diameter and thereservoir 120 generates almost 15 kPa of pressure. Because therelationship illustrated in FIG. 4 is a continuous, single-valuedfunction, any measured reservoir 120 pressure can be correlated with aunique reservoir 120 volume.

In other embodiments, the distention of the compressive sleeve spring142 and its rate of change can be directly measured to determine thereservoir 120 volume and exiting fluid flow rate. Knowledge of thecompressive sleeve spring 142 distention correlates to the reservoir 120diameter and, thus, also the reservoir volume. In such embodiments, thecompressive sleeve spring 142 preferably is made from a piezoresistivematerial. Piezoresistive materials display measurable changes in theelectrical resistance of the material based on its deformation (e.g., anincrease in the cylindrical cross section of the compressive sleevespring 142). This effect provides a direct method to measure thecompressive sleeve spring 142 expansion and, thus, the volume of thereservoir 120. Similarly, by measuring the rate of change in theresistance of the piezoresistive material, the flow rate of fluidexiting the reservoir 120 also can be determined.

In another embodiment (not shown) the pressure source 140 is applied tothe reservoir 120 by a torsion spring (not shown). The torsion spring isa multiplicity of springs in parallel that apply force to the deformableballoon 130 at different axial locations along the length of thedeformable balloon 130. In a refinement, the torsion spring does notapply an equal force at all axial locations of the deformable balloon130; the individual springs further from the outlet 144 of thedeformable balloon 130 are stiffer (i.e., they apply more force) thanthe springs near the outlet 144. The resulting force gradient in thisembodiment the deformable balloon 130 empties from the point furthestfrom the outlet 144 first, similar to a tube of toothpaste.

FIGS. 5 a and 5 b illustrate an alternate embodiment in which the twoliquid reservoirs 120 from FIG. 1 are replaced with a single liquidreservoir 220 having two reservoir chambers 234 a, 234 b. The reservoir220 includes a deformable balloon 230 (similar in construction to thedeformable balloon 130 described above) that has a deformable interiorwall 232 defining the reservoir chambers 234 a, 234 b in the interiorvolume of the deformable balloon 230. The reservoir 220 also includesoutlets 244 a, 244 b for each of the reservoir chambers 234 a, 234 b,each of which is fluidly connected to its own liquid metering unit (notshown). In general, any pressure source can be used to expel fluid fromthe reservoir chambers 234 a, 234 b, although a compressive sleevespring (not shown) is preferred. The deformable interior wall 232 allowsfluid to be withdrawn from the reservoir chambers 234 a, 234 b atdifferent rates, even though only a single reservoir 220 and singlepressure source is used. Specifically, as the compressive sleeve spring(or other pressure source) expels liquid from the reservoir 220,independent liquid metering units downstream from the outlets 244 a, 244b can be used to withdraw fluid from the reservoir chambers 234 a, 234 bat different rates because the interior wall 232 can deform toaccommodate an uneven volume distribution between the fluids remainingin the reservoir 220. For example, as illustrated in FIG. 5 b, the netflow of fluid of out the reservoir chamber 234 b is larger than that outof the reservoir chamber 234 a, and thus the interior wall 232 deflectsto the right so that the volume of the reservoir chamber 234 b (volumeof the fluid remaining in the reservoir chamber 234 b) is less than thatof the reservoir chamber 234 a.

Liquid Metering Units

The liquid metering unit 160 fluidly connected to each reservoir 120 isnot particularly limited and can include any structure or device that iscapable of controlling the flow rate of fluid exiting the reservoir 120.When the reservoir 120 includes a pressure source 140 to actively expelfluid from the reservoir 120, the liquid metering unit 160 can simplyinclude structure that attenuates the flow rate, for example a throttle(e.g., a piezoelectrically actuated microvalve), a valve (e.g., mono-,bi-, multi-stable), or a flow restrictor (e.g., a grooved plate,capillary tubing, an etched flow chip). In the absence of a pressuresource 140, the liquid metering unit 160 preferably includes a pump toactively withdraw fluid from the reservoir 120. A variety of pumps aresuitable, including, for example, peristaltic pumps (e.g., those havinga variable reservoir controlled by a valve at its inlet and outlet suchthat the upstream valve opens as the reservoir volume increases, and thedownstream valve opens as the reservoir volume reduces),magnetically-driven motor pumps, magnetohydrodynamic-based pumps,electrohydrodynamic-based pumps, ultrasonically actuated pumps, andelectro-osmotically actuated pumps. The liquid metering unit 160 alsocan include a mixer (static or otherwise; not shown) either upstream ofthe liquid metering unit 160 (e.g., in an embodiment where two or morereservoirs 120 feed fluid to a single liquid metering unit 160) ordownstream of the liquid metering unit 160 (e.g., in an embodiment whereit is desirable to actively mix the fluids exiting two or more liquidmetering units 160). In any of the above embodiments, various liquidmetering units 160 (e.g., throttles, valves, pumps) can be combined inseries or in parallel depending on a particular fluid deliveryapplication.

Preferably, the liquid metering unit 160 includes a throttle 150providing a variable hydraulic resistance so that a continuum of fluidflow rates exiting from the reservoir 120 is possible. A preferredthrottle 150 is a piezoelectrically actuated microvalve (PAM), forexample as illustrated in FIG. 2 and as described in more detail in U.S.patent application Ser. No. 11/756,342 (filed May 31, 2007), the entiredisclosure of which is incorporated herein by reference.

As illustrated in FIG. 2, the PAM throttle 150 includes a first plate154 and a second plate 152 spaced apart and joined together to define aflow path 153 having inlet fluidly connected to the liquid reservoir 120(i.e., the outlet 144 as illustrated) and an outlet catheter deliverytube 158 that is fluidly connected to the liquid delivery catheter 170(illustrated in FIG. 1). The first plate 154 is preferably asilicon-on-insulator substrate that has been etched to form a serpentinevalve seat microchannel structure (not shown) including at least onepressure sensor 155 and optionally a second pressure sensor 157. Thesecond plate 152 is preferably an etched glass plate. The PAM throttle150 also includes a piezoelectric material (e.g., a piezoelectric stack156 as illustrated) external to the flow path 153 and in contact withthe first plate 152. Preferably, the piezoelectric stack 156 is formedfrom lead zirconate titanate (PZT).

The PAM throttle 150 operates by pressing the first plate 154 againstthe second plate 152 using the piezoelectric stack 156. The spacingbetween the first and second plates 152, 154 (i.e., the gap width of theflow path 153) depends on the degree of deflection caused by thechanging height of the piezoelectric stack 156, where the height ofpiezoelectric stack 156 depends on the voltage applied thereto. Thedeflection of PZT is well known and the gap width of the flow path 153can be set to any intermediate value between the fully open gap widthand zero (i.e., when the PAM throttle 150 is closed). For example, thePAM throttle 150 gap width can be set to any value in a range of 0 μm(closed) to 8 μm (fully open) for a device suitably sized for an adulthuman.

The PAM throttle 150 has the benefit of very low power consumption. ThePZT material primarily consumes power only when the throttle 150resistance is adjusted (i.e., the height of the piezoelectric stack 156is changed). Low power consumption is ideal for use in implantablemedical devices where the replacement of a battery requires majorsurgery. Another benefit of the PAM throttle 150 is its small size. Forexample, the entire PAM throttle 150 of a device for human implantationcan be housed in a ceramic casing that is only 1.5 cm×1.5 cm×1 cm insize.

Device Control

The liquid delivery control module 180 includes several components (notindividually shown) to regulate the operation of the liquid deliveryapparatus 100 for example an electronic control system, a communicationsystem, a variety of sensors, and a power supply (e.g., a battery) topower the foregoing systems.

The electronic control system is not particularly limited and generallyincludes a microprocessor electrically connected to certain componentsof the liquid delivery apparatus 100 and memory (e.g., non-volatile) tostore various device operation programs, protocols, and data. Forexample, in the embodiment illustrated in FIGS. 1 and 2, themicroprocessor is electrically connected to the PAM throttle 150 (i.e.,to effect changes in the height of the piezoelectric stack 156 andcontrol the flow rate of fluid exiting the reservoir 120) and to thepressure sensor 155 (i.e., to read and store instantaneous pressurereadings for use in feedback control algorithms). In general, however,the microprocessor can be electrically connected to any activelycontrollable liquid metering unit 160 (e.g., a valve or pump havingvariable settings), pressure source 140 (e.g., an electrolytic fluidcell having a variable rate of bubble generation), and/or sensors usedfor feedback control/data analysis.

The communication system also is not particularly limited and caninclude a wired and/or (preferably) a wireless interface to themicroprocessor. The communication system is preferably configured fortwo-way communication such that new and/or updated programs andinstructions can be uploaded to the microprocessor and further such thatany flow rate time series data and/or any other sensed data stored inthe microprocessor memory can be downloaded to an external computer(i.e., external to the patient) for data analysis.

The specific sensors included in a given embodiment also are notparticularly limited, covering a broad range of sensors capable ofmeasuring parameters related to fluid delivery, environmental parametersrelated to the liquid delivery apparatus 100 itself, and parametersrelated to the patient. Common sensors related to fluid delivery includethose for pressure (e.g., micromachined pressure sensors) and flow rate(e.g., electromagnetic flow sensors). Environmental sensors can includeaccelerometers (e.g., shock sensors), magnetic field sensors, andtemperature sensors. Sensors used to monitor a patient's state caninclude pH sensors, glucose sensors, hormonal sensors (e.g., estrogen,testosterone); sensors for cancer-indicating proteins (e.g.,prostate-specific antigen (PSA) for prostate cancer, carcino-embryonicantigen (CEA) for uterine cancer), serotonin sensors, and dopaminesensors. Preferred sensors for inclusion in the liquid deliveryapparatus 100 include pressure sensors, flow sensors, andaccelerometers.

In an embodiment, The liquid delivery apparatus 100 and its embeddedsensors are integrated with power and control electronics in the liquiddelivery control module 180. The components of the control module 180are optimized for ease of integration while minimizing powerconsumption. Suitable commercially available products for use in theelectronic subsystems of the control module 180 exist. The communicationprotocol is preferably a 433 MHz time-duplexed binary phase shift keying(BPSK) transmission scheme with power-saving modifications. For example,the default state of the communication system is a sleep state. Thecommunication system occasionally “wakes up” from the sleep state tolisten for a start transmission signal from an external device andreciprocates the start transmission signal with a return signalcontaining synchronization data. After synchronization, the externaldevice is able to communicate information requests, re-programming(e.g., new flow rate and/or bolus delivery schedules, system self-testcommands, post-deployment calibration or recalibration),patient-controlled bolus delivery commands, or an end-transmissionsignal to the microprocessor. Any number of information requests andre-programming commands can be placed before the end-transmissionsignal, and each is executed by the liquid delivery apparatus 100 uponreception. Once the end-transmission signal is received, the liquiddelivery apparatus 100 responds with the values of the informationrequests and sends an end-transmission signal. Communication continuesback and forth in this manner until the external device sends an endcommunication command, at which time the liquid delivery apparatus 100returns to the sleep state.

Preferably, the liquid delivery pathway 110 contains one or moreembedded pressure sensors to measure the pressure of fluids beingdelivered by the liquid delivery apparatus 100. In one embodiment, thesensor is a piezoresistive, micromachined pressure sensor. The verysmall size of the piezoresistive, micromachined pressure sensor permitsa multiplicity of pressure sensors to be integrated into the liquiddelivery apparatus 100. Preferably, at least one pressure sensor islocated to measure the pressure of the fluid inside the reservoir 120.For example, as illustrated in FIG. 2, the pressure sensor 155 isembedded in the upstream portion of the PAM throttle 150 (i.e., near theinlet portion of the fluid flow path 153) to provide the pressure in thereservoir 120. Additionally, a pressure sensor can be located to measurethe pressure drop of the fluid across the liquid metering unit 160. Forexample, as further illustrated in FIG. 2, the pressure sensor 157 isembedded in the downstream portion of the PAM throttle 150 (i.e., nearthe outlet portion of the fluid flow path 153) to provide the pressuredrop across the PAM throttle 150. Such embedded sensors can providefeedback data on the time-dependent flow rate and total delivery volumethat is currently unavailable in commercial pumps, as explained in moredetail below.

Additionally, the liquid delivery apparatus 100 can contain anaccelerometer to measure and record to acceleration forces experiencedby the liquid delivery apparatus 100, which forces correspond to thoseexperienced by a patient (i.e., when the liquid delivery apparatus 100is implanted into the patient). A shock sensor is a suitable type ofaccelerometer, for example a micromachined device as described in U.S.Pat. No. 6,619,123 (the disclosure of which is incorporated herein byreference) that includes a plurality of shock sensors in an array todetect a plurality of different threshold acceleration forces.Commercially available accelerometers and algorithms of the kind oftenused in pedometers may be used, for example those available from AnalogDevices, Inc. (e.g., ADXL models; Norwood, Mass.) and FreescaleSemiconductor, Inc. (e.g., MMA models; Austin, Tex.). The accelerometerscan then be used to determine an activity level of a patient having animplanted liquid delivery apparatus 100, for example by measuring thetotal linear distance traveled (e.g., by walking) over a specified timeinterval.

Alternate Embodiments

While the foregoing describes a particular embodiment of the disclosureas illustrated in FIGS. 1, 2, and 3 a-3 d, a variety of otherarrangements of the general components described above is within thescope of the disclosure. For example, as illustrated in FIGS. 6 a-6 d, ageneral liquid delivery apparatus 300 includes a liquid delivery pathway310 having a reservoir 320 fluidly connected to a liquid metering unit360 fluidly connected to a catheter delivery tube 370 to deliver a fluidcontained in the reservoir 320 to a patient when implanted. Thereservoir 320, the liquid metering unit 360, and the catheter deliverytube 370 are analogous to the above-described components. However, thegeneral liquid delivery apparatus 300 includes a force mechanism 390that can be inserted into the flow line of the general liquid deliveryapparatus 300 at a variety of locations, which force mechanism causesany fluid within the reservoir 320 to flow toward the catheter deliverytube 370 and into the patient. For example, when the force mechanism 390is located upstream of the reservoir 320 (FIG. 6 a), the force mechanism390 can correspond to any of the above-described pressure sources 140(e.g., a compressive sleeve spring, etc.) that provide a positivepressure to expel fluid from the reservoir 320. Similarly, when theforce mechanism 390 is located upstream of the liquid metering unit 360(FIG. 6 b), downstream of the liquid metering unit 360 (FIG. 6 c), orintegrated with the liquid metering unit 360 (FIG. 6 d), the forcemechanism 390 can correspond to the above-described pumps associatedwith the liquid metering unit 160. Specifically, a force mechanism 390that is discrete from the liquid metering unit 360 (FIGS. 6 b and 6 c)can be a pump that applies a certain suction pressure to the reservoir320, while the liquid metering unit 360 (e.g., a PAM throttle)attenuates the flow rate to a desired value. Conversely, a forcemechanism 390 that is integrated with the liquid metering unit 360 (FIG.6 d, illustrated as element “360/390”) can be a positive displacementpump (e.g., aperistaltic pump) that can directly deliver and control thedesired flow rate.

The single liquid delivery pathways 310 illustrated in FIGS. 6 a-6 d canbe combined in parallel in a variety of ways to form dual (or higher)liquid delivery apparatus 300, of which FIGS. 6 c-6 j are non-limitingexamples of a representative number of combinations. For example, FIG. 6e can correspond to the embodiment of FIG. 1, where the two forcemechanisms 390 are compressive sleeve springs, the two reservoirs 320include deformable balloons, and the two liquid metering units 360 arePAM throttles. Similarly, FIG. 6 f can correspond to the embodiment ofFIGS. 5 a-5 b, where the force mechanism 390 is a single compressivesleeve spring, the two reservoirs 320 are the two reservoir chambers ofa partitioned single reservoir (i.e., and the force mechanism 390ensleeves the partitioned single reservoir), and the two liquid meteringunits 360 are PAM throttles. The remaining embodiments of FIGS. 6 g-6 jare evident with reference to the foregoing discussion and the figuresthemselves.

Operation

The disclosed liquid delivery apparatus can be used in various modes ofoperation, for example to deliver drugs to a patient or to providediagnostic information about a patient once implanted.

A preferred mode of operation includes the independent control anddelivery of two or more different medications from two or more separatereservoirs to a patient. In this case, any of the above liquid deliveryapparatus having two or more liquid delivery pathways and amicroprocessor electrically connected to the flow-control structure ofeach liquid delivery pathway (e.g., a PAM throttle and a pressure sensorto measure reservoir volume) can be used. The reservoir(s) in eachliquid delivery pathway is then charged with a medication such that atleast one liquid reservoir contains a medication that is different fromthe medication contained in another liquid reservoir. Once implantedinto a patient, the medications are delivered to the patient atindependently controlled flow rates by independently controlling theflow-control structure of each liquid delivery pathway (e.g., byactuating the PAM throttle) in response to a flow control program storedin the microprocessor.

The specific medications delivered by the liquid delivery apparatus arenot particularly limited. However, the use of a liquid deliveryapparatus having two or more separate reservoirs is particularly usefulwhen the medications to be delivered are incompatible/unstable in amixture, or when it is desirable to adjust the relative delivery ratesbetween the different medications. A preferred combination ofmedications includes at least one opioid and at least one non-opioidused for pain management. Suitable opioids include morphine,hydromorphone, fentanyl, sufentanil, meperidine, buprinorphine, andmethadone. Suitable non-opioids include adenosine, baclofen, droperidol,gabapentin, ketorolac, midazolam, neostigmine, octreotide, andziconotide. A particularly preferred opioid/non-opioid combinationincludes morphine and baclofen. Other suitable uses for the disclosedliquid delivery apparatus include the delivery of local anesthetics(e.g., bupivacaine, ropivacaine, tetracaine), adrenergic agonists (e.g.,clonidine, moxonidine), N-methyl-D-aspartate (NMDA) antagonists (e.g.,ketamine), chemotherapy drugs (e.g., hepatic artery infusion5-fluorouracil (“5-FU”), melphalan, and/or cisplatinum), andantibiotics.

In the embodiment described in relation to FIGS. 1 and 2, the deliveryflow rate of a fluid from the reservoir 120 can be controlled bymeasuring the reservoir 120 pressure. As illustrated in FIG. 4, thevolume of fluid in the reservoir 120 is correlated with the reservoir120 pressure. Accordingly, time series measurements of the reservoir 120pressure (e.g., via the pressure sensor 155) can be converted to anequivalent time series of the reservoir 120 fluid volume, and the changein fluid volume over a specified measurement time interval (ΔV/Δt) canbe computed (e.g., using the microprocessor) to estimate theinstantaneous fluid delivery flow rate. By computing the instantaneousfluid delivery flow rate, the microprocessor can then actuate the PAMthrottle 150 to adjust the flow rate to a desired value, based on aprogram stored in the microprocessor. For example, it may be desirableto deliver: (1) a constant or substantially constant fluid flow rateover an indefinite period, (2) a fixed-volume bolus of fluid over adiscrete period, or (3) combinations thereof. When a substantiallyconstant fluid flow rate is desired, the pressure sensor 155 is used toconstantly monitor the fluid flow rate; when the fluid flow rate dropsbelow a specified value (i.e., due to the reduction in reservoir 120pressure as the reservoir 120 empties), the microprocessor actuates andfurther opens the PAM throttle 150 so that it provides a lowerresistance to flow, thereby increasing fluid flow rate back to a desiredset point. When a fixed-volume bolus is desired, the initial reservoir120 fluid volume can be measured using the pressure sensor 155, the PAMthrottle 150 can be opened to release fluid, and the PAM throttle 150can be subsequently closed once the reservoir 120 fluid volume hasdropped by an amount corresponding to the desired fixed-volume bolus(i.e., as determined by ongoing pressure measurements).

The disclosed liquid delivery apparatus can also provide objectivediagnostic information about a patient, for example by optimizing thedosage level of a plurality of medications to a patient during atitration stage of therapy. When a general multi-reservoir liquiddelivery apparatus having an accelerometer is charged with two or moredifferent medications and is implanted in the patient, the patient'sactivity levels over specific periods can be monitored to identifyoptimum dosage levels of each medication. Once the optimum dosage levelsare determined, each of the medications can be delivered to the patientin combination and at their respective optimum levels to achieve themaximum therapeutic benefit with the minimum effective doses.

For example, when the liquid delivery apparatus contains a first andsecond medication, a first activity level of the patient is monitored toidentify a first optimum dosage level of the first medication, and thena second activity level of the patient is monitored to identify a secondoptimum dosage level of the second medication. In this optimizationcontext, a medication can be a single component or a blend of components(e.g., the first medication could be a blend of two opioids, while thesecond medication could be a single non-opioid). Both monitoring stepspreferably include delivering only one medication to the patient at aplurality of dosage levels for a preselected length of time; using theaccelerometer to measure and record the patient's activity at each ofthe dosage levels; and, then selecting the optimum dosage level based onthe dosage level that provides the greatest activity level.

FIGS. 7 a-7 c illustrate hypothetical optimization and monitoring stepsin more detail, for example when a patient's activity level is measuredusing the accelerometer in terms of the total distance the patient walksin successive one-week periods during which periods the dosage level ofthe delivered medication is substantially constant.

FIG. 7 a illustrates the first monitoring step in which only the firstmedication (e.g., an opioid) is delivered to the patient at successivelyincreasing, substantially constant dosages f₁, f₂, f₃, and f₄, where thedosages are altered at weekly intervals by a physician (or in responseto a programmed dosage sequence in the microprocessor), generally atleast until a local maximum in the activity level is identified. Duringthe first monitoring step, the accelerometer constantly monitors andstores the patient's activity level, illustrated in FIG. 7 a inarbitrary activity units (e.g., distance walked). Once patient activitydata as a function of dosage level is obtained, the physician cantabulate, plot, or otherwise analyze the data to estimate thepatient-specific optimum dosage level of the first medication (i.e., thedosage level at which the therapeutic benefit of the medication ismaximized, prior to the onset of any debilitating effects from amedication overdose). As illustrated in FIG. 7 a, f₃ is the estimatedoptimum dosage level of the first medication with an activity of 4units. Depending on the interval spacing of the dosage test levels f₁,f₂, f₃, and f₄, it may be desirable to perform further monitoring stepsfor the first medication to more accurately estimate the optimum (i.e.,by testing more dosage levels between f₂ and f₄ in the exampleillustrated in FIG. 7 a).

FIG. 7 b illustrates the analogous second monitoring step in which onlythe second medication (e.g., a non-opioid) is delivered to the patientat successively increasing, substantially constant dosages s₁, s₂, s₃,s₄, s₅, and s₆ over weekly intervals. As illustrated in FIG. 7 b, s₃ isthe estimated optimum dosage level of the first medication with anactivity of 2 units.

Once the optima f₃ and s₃ are identified, the liquid delivery apparatuscan be reprogrammed by the physician so that it simultaneously deliversthe first medication at f₃ and the second medication at s₃. Oncesimultaneous delivery of the two medications is initiated, the patient'sactivity can be further monitored to verify that the two medications incombination provide an additive, net beneficial effect. As illustratedin FIG. 7 c, the two medications can exhibit an additive, synergisticeffect (i.e., the combination of medications results in an activitylevel of 6 or more units, which is at least as high as added activitylevels of 4 units and 2 units resulting from the use of only a singlemedication). However, even if no synergistic effect is observed, theadditional monitoring step can be performed to verify that at least someadditive benefit is obtained by using the two medications in combination(i.e., to verify that the combination of medications results in anactivity level of more than 4 units, which is greater than the use ofany single medication alone).

Example

Various components of the liquid delivery apparatus 100 according to thedisclosure and as illustrated in FIGS. 1, 2, and 3 a-3 d were assembledand tested to determine their ability to reliably deliver independentlycontrolled volumes of fluid.

A reservoir 120 was formed from a polyethylene terephthalate (PET)balloon 130 using a compressive sleeve spring 142 as a pressure source140. The compressive sleeve spring 142 was made from a 45% cold-reducedCo/Ni/Cr ELGILOY alloy in a planar sheet. A metal compressive sleevespring 142 was used because it is small, offers comparable pressures totraditional springs, and undergoes gradual degradation instead ofcritical failure. The compressive sleeve spring 142 was fabricated bylaminating the sheet of ELGILOY alloy with a photoresist, patterning thephotoresist, and then chemically etching the alloy to form the planarspring illustrated in FIGS. 3 a and 3 b (i.e., 100 μm thickness, 150 μmwide beams, with a mesh cell size of 600 μm by 6 mm). The etched planarsheet was then conditioned by stretching to a 100% elongation state,after which the etched, conditioned planar sheet had a repeatable springconstant of about 306 N/m. The etched, conditioned planar sheet was thenrolled into a sleeve and the seams were epoxy bonded to form thecompressive sleeve spring 142 illustrated in FIGS. 3 c and 3 d (i.e., acylindrical sleeve about 60 mm long with about a 6 mm diameter). The PETballoon 130 had a length of about 60 mm and a diameter of about 20 mmwhen inflated (i.e., an inflated capacity of about 18.8 ml as comparedto un-pressurized volume of 4.7 ml). The PET balloon 130 was theninserted into the compressive sleeve spring 142 and inflated to a 20 mmdiameter (FIG. 3 d) with a liquid (water).

The relationship between the reservoir 120 volume and pressure is acalibration parameter used to control the volume of fluid delivered bythe liquid delivery apparatus 100, whether as a fixed-volume bolus orover a period at a substantially constant flow rate. Tests wereconducted in which the reservoir 120 was inflated with a liquid, and theresulting pressure and diameter of the reservoir 120 were monitored. Theliquid was pressurized with nitrogen, and the reservoir 120 diameter wasmeasured using micro-calipers. During inflation, the reservoir 120diameter changed linearly, typically from about 12 mm to about 19 mm asthe compressive sleeve spring 142 provided the pressurizing force.Beyond 19 mm, the elasticity of the PET balloon 130 changed the pressuregeneration curve. When fully inflated, the reservoir 120 generated about15 kPa.

The gauge factor (ratio of fractional change in resistance to fractionalchange in length) for most bulk metals is 1-10. Thus, the ELGILOY alloyused to form the compressive sleeve spring 142 (or other piezoresistivematerial) could be used as a strain gauge to measure distention (i.e.,and diameter as well) in the PET balloon 130. Such measurement of thediameter of the PET balloon 130 could be used in place of or in additionto the pressure sensor 155 as an additional method for determining theinstantaneous volume of fluid contained in the reservoir 120.

A PAM throttle 150 substantially as described above and having a PZTpiezoelectric stack 156 was fabricated for testing with the fabricatedreservoir 120. The PAM throttle 150 was housed in a 1.5 cm×1.5 cm×1 cmceramic casing and was capable of attaining a gap width ranging from 0μm to 8 μm between the first and second plates 152, 154 of the PAMthrottle 150. Actuation of the PAM throttle 150 to change the gap widthfrom a first value to a second value in the 0 μm to 8 μm range could beperformed at voltages up to 120 V and required 376.8 μJ per change(though a semi-empirical estimate of the required energy is about 9.2 mJper charge). At rest, the PAM throttle 150 consumed about 34 nA or less.Thus, the total power consumption of the PAM throttle 150 is acombination of its continuous power draw and the added consumption ofany actuation events.

The known characteristics of the reservoir 120 and the PAM throttle 150allow multiple modes of flow regulation and allow the delivery ofsubstantially constant flow rates based on a compromise between flowrate accuracy and power consumption of the liquid delivery apparatus100.

As described and illustrated above, pressure (P), which is the pressureat the point of delivery, is generated as a continuous function of thevolume (V) of the reservoir 120 (i.e., P=f(V); FIG. 4). The flow rate(Q) from the reservoir 120 is related to the differential pressurebetween the reservoir 120 and the delivery load through the hydraulicresistance of the serial combination of the PAM throttle 150 and theliquid delivery catheter 170. For an unactuated, open PAM throttle 150,the minimum hydraulic resistance is 7.32×10¹² Pa·s/m³ (R_(Throttle)),which is about 10 times the resistance for a 1 m catheter (6.519×10¹¹Pa·s/m³). Therefore, the hydraulic resistance of the PAM throttle 150approximately defines the net hydraulic resistance of the liquiddelivery apparatus 100 (R_(system)). Accordingly, the fluid deliveryflow rate can be regulated by changing hydraulic resistance of the PAMthrottle 150:

$\begin{matrix}{Q = {{\frac{P}{R_{System}} \approx \frac{P}{R_{Throttle}}} = {- {\frac{\partial\left\lbrack {f^{- 1}(P)} \right\rbrack}{\partial t}.}}}} & {{Eqn}.\mspace{14mu} (1)}\end{matrix}$

The flow rate is the change in volume with time and can be expressed asa function of pressure. Therefore, the delivery flow rate can bedetermined by monitoring the change in reservoir pressure over timeusing the pressure sensor 155. Such a control mechanism requires noinformation about the PAM throttle 150 for accurate flow regulation, andit can be used to regulate a fixed-volume bolus delivery from thereservoir 120. For the tested PAM throttle 150, the highest possibleactuation voltage was 120 V, which resulted in a flow rate of 5.0 ml/dayand required a minimum pressure difference (ΔP) of 130 Pa.

Another control mechanism involves setting the PAM throttle 150 to afixed gap width and periodically opening it further to maintain a setflow rate as the reservoir 120 pressure drops. For a particular PAMthrottle 150 set point, the hydraulic resistance is constant. Asindicated in Eqn. 1, the flow rate is the reservoir 120 pressure dividedby the hydraulic resistance, and the reservoir 120 pressure changes asmaterial flows from it, so the flow rate for a particular set point is afunction of time:

$\begin{matrix}{Q = {{Q_{set} + Q_{err}} = {\frac{P(t)}{R_{Throttle}} = {{h(t)}.}}}} & {{Eqn}.\mspace{14mu} (2)}\end{matrix}$

For a constant PAM throttle 150 set point, there is a set flow rate(Q_(set)) and an acceptable deviation from this set point (Q_(err)) suchthat the flow rate remains within an acceptable error range. The flowrate function h(t) will slowly decay because the reservoir 120 pressuredrops as it empties. The initial time (t_(a)) and the final time (t_(b))that the flow rate will be within the error bounds for a particular setpoint can be determined:

t _(a) =h ⁻¹(Q _(set) +Q _(err)); t _(b) =h ⁻¹(Q _(set) −Q _(err))  Eqn. (3)

Thus, given a desired set flow rate (Q_(set)) and accuracy level(Q_(err)/Q_(set); e.g., about 10% or less, preferably about 5% or less,1% or less, or 0.2% or less), the time interval (t_(a)-t_(b)) over whichthe PAM throttle 150 can remain in a given state can be determined; thistime interval similarly dictates the frequency with which the PAMthrottle 150 is actuated to obtain a substantially constant flow rate.

For example, the typical range of delivery for intrathecal morphinevaries from about 0.2 ml/day to about 5.0 ml/day. Analytical modelsbased on empirical data from the PAM throttle 150 and the reservoir 120with the compressive sleeve spring 142 were used to simulate drugdelivery from the liquid delivery apparatus 100 at various constant flowrates. FIG. 8 illustrates the results of these simulations at varyingerror rates over one day (i.e., Q_(err)/Q_(set)=5%, 1%, and 0.2%). Theactuated frequency for delivering 0.2 mL/day with a 5% error is 2.1adjustments/day (FIG. 8, top). The primary power draw at such aswitching frequency is the leakage through the PAM throttle 150.Conversely, the highest computed power consumption scenario requires oneadjustment every four minutes to regulate 5.0 mL/day with 0.2% accuracy(FIG. 8, bottom), and the resulting power draw of the PAM throttle 150is 1.68 μW. Thus, the disclosed liquid delivery apparatus 100 isflexible in that it can operate very energy-efficiently when high levelsof accuracy are not required; conversely, it is capable of operating athigh levels of accuracy when needed, albeit at the cost of increasedenergy consumption.

The fabricated combination of the PAM throttle 150 and the reservoir 120was also tested to characterize the ability of the combination toreliably deliver fixed-volume bolus doses of fluid. Because theprogressive reduction of the reservoir 120 pressure accompanies thedelivery of any volume of fluid, and further because the relationbetween pressure and volume is known, a bolus regulation program cancalculate the PAM throttle 150 aperture and timing based on pressuremeasurements. For example, the PAM throttle 150 is opened to begin bolusdelivery, and after the prescribed pressure drop that corresponds to thedesired fixed bolus volume is observed, the valve is closed. FIG. 9illustrates a delivery of 6 ml over four 1.5 ml bolus doses. The initialvolume is determined using inlet pressure, and the stop pressure iscalculated from the reservoir 120 pressure-volume relationship. FromFIG. 9, it is apparent that a liquid delivery apparatus using the PAMthrottle 150 and the reservoir 120 is capable of accurately delivering aspecified fixed-volume bolus of fluid, regardless of whether thedelivery time is on the order of about 10² s or about 10³ s.

A liquid delivery apparatus 100 constructed from the fabricated PAMthrottle 150 and reservoir 120 would be both compact andvolume-efficient. For example, an external housing having a total volumeof 73.9 ml (8.8 cm×4.8 cm×1.75 cm) has sufficient space for two liquiddelivery paths 110 (i.e., each requiring 18.8 ml for the reservoir 120and 2.25 ml for the PAM throttle 150) and enough additional space for aliquid delivery control module 180 including a microprocessor,circuitry, a battery, etc. The volume efficiency and estimated weight ofsuch a device is 0.51 (i.e., 2×18.8 ml/73.9 ml) and about 80 g. Asillustrated in Table 1, the disclosed liquid delivery apparatus 100 is(1) more compact and volume-efficient than commercially availableintrathecal pumps and (2) more versatile that the commercially availableintrathecal pumps (i.e., because they only provide single-reservoirdevices). Further, the disclosed liquid delivery apparatus is energyefficient relative to other battery-powered devices, such thatconventional battery technology used in the disclosed device can powerthe device at least about 2 to 3 times longer than a battery-poweredcommercially available intrathecal pump. In Table 1, multiple columnsfor a single device indicate the commercially available range of sizesfor a particular model.

TABLE 1 Comparison of Disclosed Liquid Delivery Apparatus withCommercially Available Intrathecal Pumps Medtronic Medtronic CodmanDevice Disclosed Device SYNCHROMED EL ISOMED CODMAN 3000 Reservoir TypeDual Single Single Single Device Volume (ml) 73.9   123 157 112 135 17294.1 162 219 Reservoir Vol. (ml) 2 × 18.8 10 18 20 35 60 16 30 50 VolumeEfficiency 0.509 0.081 0.115 0.178 0.259 0.348 0.170 0.185 0.228 DeviceWeight (g) 80    185 205 113 116 120 98 137 173 Battery Life (yr) 15+  5 to 7 No battery No battery Flow Rates (ml/day) 0.1 to 30 (each; 0.5 to20 0.3, 0.5, 1.0, 1.5, 0.3, 0.5, 1.0, 1.7 programmable) (programmable)4.0 (constant flow) (constant flow)

In view of the foregoing, the disclosed liquid delivery apparatuspossesses several advantages relative to conventional intrathecal pumps.Regardless of whether the liquid delivery apparatus is configured with asingle fluid reservoir or two or more fluid reservoirs, the disclosedapparatus is highly compact, volume-efficient, and energy-efficient.Similarly, the liquid delivery apparatus having any number of reservoirsis capable of accurately delivering fluid (1) at constant orsubstantially constant flow rates and/or (2) as a fixed-volume bolus.When the liquid delivery apparatus includes two or more fluidreservoirs, the fluid flow rate from each reservoir can be independentlycontrolled, and potential complications due to medicationincompatibilities can be avoided. Further, the inclusion of two or morefluid reservoirs permits an optimization of the dosage level fordifferent medications in each of the reservoirs.

Because other modifications and changes varied to fit particularoperating requirements and environments will be apparent to thoseskilled in the art, the invention is not considered limited to theexample chosen for purposes of disclosure, and covers all changes andmodifications which do not constitute departures from the true spiritand scope of the invention.

Accordingly, the foregoing description is given for clearness ofunderstanding only, and no unnecessary limitations should be understoodtherefrom, as modifications within the scope of the invention may beapparent to those having ordinary skill in the art.

Throughout the specification, where the compositions, processes, orapparatus are described as including components, steps, or materials, itis contemplated that the compositions, processes, or apparatus can alsocomprise, consist essentially of, or consist of, any combination of therecited components or materials, unless described otherwise.Combinations of components are contemplated to include homogeneousand/or heterogeneous mixtures, as would be understood by a person ofordinary skill in the art in view of the foregoing disclosure.

1. A liquid delivery apparatus comprising a liquid delivery pathway, theliquid delivery pathway comprising: a liquid reservoir comprising adeformable balloon and a pressure source selected from the groupconsisting of a compressive sleeve spring and an electrolytic fluidcell; a liquid metering unit fluidly connected to the liquid reservoir;and, a catheter delivery tube fluidly connected to the liquid meteringunit.
 2. The liquid delivery apparatus of claim 1, wherein: the liquidmetering unit comprises a throttle; and, the liquid delivery pathwayfurther comprises a means for measuring the volume of the liquidreservoir.
 3. The liquid delivery apparatus of claim 2, wherein themeans for measuring the volume of the liquid reservoir comprises apressure sensor fluidly connected to the liquid reservoir between theliquid reservoir and the liquid metering unit throttle.
 4. The liquiddelivery apparatus of claim 2 further comprising a liquid deliverycontrol module, the liquid delivery control module comprising: amicroprocessor electrically connected to the throttle and the means formeasuring the volume of the liquid reservoir; and, a batteryelectrically connected to the microprocessor.
 5. The liquid deliveryapparatus of claim 4, comprising a plurality of liquid deliverypathways, wherein the microprocessor is capable of independentlycontrolling liquid flow through each liquid delivery pathway.
 6. Theliquid delivery apparatus of claim 2 further comprising a plurality ofliquid delivery pathways.
 7. The liquid delivery apparatus of claim 6,comprising a liquid delivery catheter fluidly connected to the catheterdelivery tube of each of the plurality of liquid delivery pathways. 8.The liquid delivery apparatus of claim 1, wherein the compressive sleevespring comprises a piezoresistive material.
 9. (canceled)
 10. The liquiddelivery apparatus of claim 2, wherein the throttle comprises apiezoelectrically actuated microvalve.
 11. The liquid delivery apparatusof claim 10, wherein the piezoelectrically actuated microvalvecomprises: a first plate and a second plate spaced apart and joinedtogether to define a flow path having an inlet fluidly connected to theliquid reservoir and an outlet fluidly connected to the catheterdelivery tube; and, a piezoelectric material external to the flow pathand in contact with the first plate.
 12. The liquid delivery apparatusof claim 11, wherein: the first plate comprises a silicon-on-insulatorsubstrate; the second plate comprises glass; and, the piezoelectricmaterial comprises lead zirconium titanate.
 13. The liquid deliveryapparatus of claim 1, wherein the liquid reservoir further comprises arefill port.
 14. The liquid delivery apparatus of claim 1 furthercomprising a bolus port fluidly connected to the catheter delivery tube.15. A liquid delivery apparatus comprising a plurality of liquiddelivery pathways, each liquid delivery pathway comprising: a liquidreservoir; a piezoelectrically actuated microvalve fluidly connected tothe liquid reservoir; and, a catheter delivery tube fluidly connected tothe piezoelectrically actuated microvalve. 16.-22. (canceled)
 23. Aliquid delivery apparatus comprising a liquid delivery pathway and asensor selected from the group consisting of a flow meter fluidlyconnected to the liquid delivery pathway, an accelerometer, andcombinations thereof; wherein the liquid delivery pathway comprises: aliquid reservoir; a liquid metering unit fluidly connected to the liquidreservoir; and, a catheter delivery tube fluidly connected to the liquidmetering unit. 24.-26. (canceled)
 27. The liquid delivery apparatus ofclaim 23, wherein: the liquid reservoir comprises a deformable balloonand a pressure source selected from the group consisting of acompressive sleeve spring, a torsion spring, and an electrolytic fluidcell; the liquid metering unit comprises a throttle; and the liquiddelivery pathway further comprises a means for measuring the volume ofthe liquid reservoir. 28.-30. (canceled)
 31. A liquid delivery apparatuscomprising: a liquid reservoir comprising a deformable balloon having aninterior volume and at least one deformable interior wall in theinterior volume, the at least one deformable interior wall defining aplurality of reservoir chambers in the interior volume; a plurality ofliquid metering units, each of which is fluidly connected to one of thereservoir chambers; and, a plurality of catheter delivery tubes, each ofwhich is fluidly connected to one of the liquid metering units.
 32. Theliquid delivery apparatus of claim 30, wherein the liquid reservoirfurther comprises a pressure source selected from the group consistingof a compressive sleeve spring, a torsion spring, and an electrolyticfluid cell; and each liquid metering unit comprises a throttle.
 33. Theliquid delivery apparatus of claim 31, further comprising a means formeasuring the volume of the liquid in the reservoir chambers.
 34. Theliquid delivery apparatus of claim 32, further comprising a liquiddelivery control module, the liquid delivery control module comprising:a microprocessor electrically connected to the throttle and the meansfor measuring the volume of the liquid in the reservoir chambers; and abattery electrically connected to the microprocessor. 35.-39. (canceled)